Ubiquitin-specific-processing protease 14 (USP14)

Ubiquitin-specific-processing protease 14 (USP14) is a major deubiquitinating enzyme (DUB) that reversibly associates with the 19S regulatory particle of the 26S proteasome. It plays a dual role in proteostasis by trimming ubiquitin chains from substrates to facilitate their entry into the proteasome or by inhibiting degradation through premature deubiquitination. USP14 is typically autoinhibited in its free form and becomes catalytically active only upon binding to the proteasome. In oncology, USP14 is frequently overexpressed and contributes to tumor progression by stabilizing oncogenic proteins and inhibiting apoptosis. Conversely, in neurodegenerative contexts, inhibiting USP14 has been shown to accelerate the clearance of misfolded proteins such as tau and ataxin-3. Consequently, USP14 has emerged as a significant therapeutic target, with small-molecule inhibitors like IU1 being developed to modulate protein turnover in various diseases.

Other names

TGTDeubiquitinating enzyme 14Ubiquitin carboxyl-terminal hydrolase 14Ubiquitin thioesterase 1426S proteasome-associated deubiquitinase USP14

Inhibition of deubiquitinating activity to accelerate proteasomal degradation of substrates or induce proteotoxic stress in cancer cells